More than two decades ago, our lab established the class II transactivator (CIITA) as a master transcriptional regulator of all class II Major Histocompatibility Complex (MHC) genes. We subsequently searched the human genome and found that CIITA has over twenty family members, which now constitute the large NLR (Nucleotide-binding domain leucine-rich repeat containing, or Nucleotide-oligomerization domain-like receptors) gene family. NLRs are considered cytoplasmic intracellular sensors of pathogenic products; however, more data have emerged suggesting that they also respond to damage-associated molecular patterns and modulate several intracellular signaling pathways. This proposal focuses on a member of the NLR family, NLRC5, that has an N-terminal CARD domain, a central nucleotide binding domain (NBD) and a series of C- terminal leucine-rich repeats. Studies using cell lines established NLRC5 as a positive regulator of MHCI transcription and as an inhibitor of innate immune signaling, especially the NF?B pathway. NF?B directly controls the transcription of proinflammatory cytokines (e.g. IL-6, TNF, IL-1?) in response to pathogen-associated molecular patterns (PAMPs). NLRC5 sequesters the I?B kinases (IKK?/?) whose activity is required for degradation of I?B and subsequent nuclear translocation of NF?B transcription factors. We and several other laboratories independently generated Nlrc5-/- mouse strains and found that NLRC5 indeed regulates class I MHC gene transcription. Some labs also found a role for this protein in the production of proinflammatory cytokines in response to TLR ligands. We will explore how these different phenotypes might be regulated by NLRC5 through continued study of Nlrc5-/- mice. The balance of pro- and anti-inflammatory responses is critical for re-establishing homeostasis following pathogen clearance and inflammatory diseases. The studies in this proposal have broader implications for the NLR field as a whole since we hope to reveal a universal mechanism for NLRs to mediate divergent functions.